Agios Pharmaceuticals : ENERGIZE Phase 3 Topline Results

Topline Results:

Phase 3 ENERGIZE Study of

PYRUKYND® (mitapivat) in Thalassemia

January 3, 2024

Agios conference call participants

TOPIC	PARTICIPANT
Opening Remarks	Brian Goff, Chief Executive Officer
Data Highlights from Phase 3 ENERGIZE Study	Jeremie Estepp, M.D., Medical Director
Framing Phase 3 ENERGIZE-T Study Readout	Sarah Gheuens, M.D., Ph.D., Chief Medical Officer,
Head of Research and Development
Closing Remarks	Brian Goff, Chief Executive Officer
Q&A	Mr. Goff, Dr. Estepp, Dr. Gheuens, Cecilia Jones (CFO),
and Tsveta Milanova (CCO)

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Forward-looking statements

This presentation and various remarks we make during this presentation contain forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements include those regarding: the potential benefits of mitapivat; Agios' plans for the future clinical development of mitapivat in alpha-and-beta thalassemia; and Agios' strategic plans and prospects. The words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "would," "could," "potential," "possible," "hope" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such statements are subject to numerous important factors, risks and uncertainties that may cause actual events or results to differ materially from Agios' current expectations and beliefs. For example, there can be no guarantee that any product candidate Agios or its collaborators is developing will successfully commence or complete necessary preclinical and clinical development phases, or that development of any of Agios' product candidates will successfully continue. Moreover, there can be no guarantee that any medicines ultimately commercialized by Agios will receive commercial acceptance. There can be no guarantee that any positive developments in Agios' business will result in stock price appreciation. Management's expectations and, therefore, any forward-looking statements in this presentation and various remarks we make during this presentation could also be affected by risks and uncertainties relating to a number of other important factors, including, without limitation: risks and uncertainties related to the impact of pandemics or other public health emergencies to Agios' business, operations, strategy, goals and anticipated milestones, including its ongoing and planned research activities, ability to conduct ongoing and planned clinical trials, clinical supply of current or future drug candidates, commercial supply of current or future approved products, and launching, marketing and selling current or future approved products; Agios' results of clinical trials and preclinical studies, including subsequent analysis of existing data and new data received from ongoing and future studies; the content and timing of decisions made by the U.S. FDA, the EMA

or other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; Agios' ability to obtain and maintain requisite

regulatory approvals and to enroll patients in its planned clinical trials; unplanned cash requirements and expenditures; Agios' ability to obtain, maintain and enforce patent and other intellectual property protection for any product candidates it is developing; Agios' ability to establish and maintain key collaborations; uncertainty regarding any milestone or royalty payments related to the sale of Agios' oncology business or its in-licensing of TMPRSS6 siRNA, and the uncertainty of the timing of any such payments; uncertainty of the results and effectiveness of the use of proceeds from the transaction with Servier; competitive factors; and general economic and market conditions. These and other risks are described in greater detail under the caption "Risk Factors" included in Agios' public filings with the Securities and Exchange Commission. Any forward-looking statements contained in this presentation and various remarks we make during this presentation speak only as of the date hereof, and Agios expressly disclaims any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

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Opening Remarks

Brian Goff

Chief Executive Officer

Data Highlights from Phase 3

ENERGIZE Study

Jeremie Estepp, M.D.

Medical Director at Agios

There are no approved oral treatments for non-transfusion-dependent thalassemia (NTDT)

• Thalassemia is a group of genetic disorders impacting α- and/or β-globin genes, resulting in an imbalance of globin production1,2
• • Excess globin chains precipitate and are toxic to red blood cells (RBCs), directly leading to ineffective erythropoiesis and hemolysis2
• Thalassemic RBCs lack sufficient levels of ATP to meet the increased energy demands associated with degradation of globin chain precipitates and cellular oxidative stress responses3,4
• Although patients with non-transfusion-dependent thalassemia (NTDT) do not require regular blood transfusions for survival, they can experience chronic anemia and serious complications1,2
• • Treatment options for NTDT are supportive only, highlighting an unmet need for disease-modifying therapies5
• Mitapivat is an investigational, first-in-class, oral, small-molecule allosteric activator of pyruvate kinase (PK) in RBCs, a key enzyme that regulates ATP production6

PYRUKYND® is approved in the U.S., EU, and Great Britain for adult PK deficiency and is under investigation for pediatric PK deficiency, thalassemia, and sickle cell disease.

ATP, adenosine triphosphate; NTDT, non-transfusion-dependent thalassemia; PK, pyruvate kinase; RBC, red blood cell; 1. Taher AT et al. Lancet 2018;391:155-67; 2. Galanello R et al. Orphanet J Rare Dis

6 2010;5:11; 3. Khandros E et al. Blood 2012;119:5265-75; 4. Shaeffer JR. J Biol Chem 1988;263:13663-9; 5. Musallam KM et al. Haematologica 2021;106:2489-92; 6. Kung C et al. Blood 2017;130:1347-56

PYRUKYUND® (mitapivat) is an oral, small molecule allosteric activator of pyruvate kinase with the potential to correct RBC metabolism

						Glycolysis
						Glucose
Hexokinase (HK) catalyzes the			HK
		Glucose-6-Phosphate
first step in glycolysis
						Frucose-6-Phosphate
						FBP
2,3-DPG is an important						1,3-DPG
regulator of the oxygen			2,3-DPG	3-PG
affinity of Hb3
						PEP

ADP

PK activation is expected to correct RBC metabolism by:

Normalizing the PK/HK ratio -

Decreased PK/HK ratio is observed in MDS

Reducing 2,3-DPG levels -

Elevated 2,3-DPG levels are associated with RBC sickling in SCD

Increasing RBC energy production (ATP)

PK catalyzes the final step in glycolysis to generate ATP, which is essential for RBC function and stability1,2

PKR

ATP

Pyruvate

PK

Activator

- Reduced

ATP production and/or increased ATP demand is observed in PKD, thalassemia, SCD, and LR-MDS

ADP = adenosine diphosphate; ATP = adenosine triphosphate; DPG = diphosphoglycerate; FBP = fructose bisphosphate; m = mutant; PEP = phosphoenolpyruvate; PG = phosphoglycerate; PK = pyruvate

7 kinase; PKR = RBC-specific PK; RBC = red blood cell

1. Kung C et al. Blood 2017;130:1347; 2. Valentini G et al. J Biol Chem 2002;277:23807; 3. Rab MAE et al. Blood 2021;137:2997-3001

Two global, Phase 3, randomized controlled trials of PYRUKYND® in thalassemia encompass broad range of thalassemia patients

N = 171

2:1 randomization

100 mg BID		Placebo BID

24-week core period

Open-label extension (up to 5 years)

N = 240

2:1 randomization

100 mg BID		Placebo BID

48-week core period

Open-label extension (up to 5 years)

Primary endpoint

• Mean Hb ↑
  ≥ 1 g/dL from baseline

Secondary endpoints

• Fatigue, additional measures of Hb ↑, hemolysis, patient- reported outcomes, physical activity, iron metabolism, safety, PK/PD

Key inclusion criteria

• ≥ 18 years
• β-thalassemia± α-globin mutations, HbE β-thalassemia, or α-thalassemia (HbH disease)
• Non-transfusion-dependentdefined as ≤5 RBC units during the 24-week period before randomization and no RBC transfusions ≤8 weeks prior
• Hb ≤ 10.0 g/dL

Primary endpoint

• 50% reduction in transfusion burden in any 12-week rolling period

Secondary endpoints

• Additional measures of transfusion reduction, safety, PK/PD

Key inclusion criteria

• ≥ 18 years
• β-thalassemia± α-globin mutations, HbE β-thalassemia, or α-thalassemia (HbH disease)
• Transfusion-dependentdefined as 6 to 20 RBC units transfused and ≤6-weektransfusion-free period during the 24-week period before randomization

BID = twice daily; Hb = hemoglobin; HbE = hemoglobin E; HbH = hemoglobin H; PK = pharmacokinetics; PD = pharmacodynamics.

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Phase 3 ENERGIZE study: primary endpoint achieved

• Total of 194 patients were randomized 2:1 to 100 mg mitapivat (n=130) or placebo (n=64)
• Hemoglobin response is defined as ≥1.0 g/dL (10 g/L) increase in average Hb concentrations from Week 12 through Week 24 compared with baseline.
• Treatment with mitapivat demonstrated a statistically significant increase in

hemoglobin response rate compared to placebo

	Primary Endpoint	Placebo	Mitapivat 100 mg BID
	N=64	N=130
	Hemoglobin responders, n (%)	1 (1.6)	55 (42.3)
	Adjusted difference of response rate		40.9
	(Mitapivat-Placebo), %
	95% CI		(32.0, 49.8)
	2-sidedp-value		<0.0001
	Abbreviations: RBC = red blood cell; Hb = hemoglobin. Subjects who do not have at least 2 on-treatment Hb concentration assessments between Week 12 and Week 24 are considered non-responders.
	Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized
	and dosed.
	Hb concentrations assessed within 8 weeks after an RBC transfusion are excluded from the baseline derivation and from the analysis.
9	The estimated adjusted difference in response rate, 95% CI and p-value are based on Mantel-Haenszel stratum weighted method adjusting for the randomization stratification factors.

Statistical significance also achieved for both key secondary endpoints

Key secondary endpoints: change from baseline in both FACIT-Fatigue Score and hemoglobin concentration

• Change from baseline in average FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue) subscale score from Week 12 to Week 24
• Change from baseline in average hemoglobin concentration from Week 12 to Week 24
• Treatment with 100 mg mitapivat demonstrated statistically significant improvements on both key secondary endpoints compared to placebo

Safety

• Overall, during the 24-weekdouble-blind period, incidence of adverse events was similar across mitapivat and placebo arms
• Four (3.1%) subjects in the mitapivat arm experienced adverse events (AEs) leading to discontinuation; there were no AEs in the placebo arm leading to discontinuation

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